The University of Pittsburgh Multicenter AIDS Cohort Study (Pitt MACS) Clinical Research Site (CRS) was established in 1983 by Dr. C. Rinaldo, PI, as one of 4 MACS CRS as a prospective cohort study of the natural history of HIV infection and the impact of effective combination antiretroviral therapies (cART) in men who have sex with men (MSM). We will continue to combine genetic, virologic, immunologic and psychosocial approaches and utilize the specimen cryorepository for long-term characterization of Pitt MACS participants. Along with our new satellite clinic site at The Ohio State University (OSU) led by Dr. S. Koletar, we will continue follow-up of the cohort with a dynamic enrollment to enable further elucidation of the biology and response to HIV infection, and distinguishing the effects of age, HIV, evolving cART regimens, genetics, co- infections and behavior use on clinical outcomes and causally-associated biomarkers. This is a transition to a rolling cohort design to replace existing cohort members who die or otherwise are permanently lost to follow-up. The Pitt MACS scientific agenda focuses on clinical epidemiology, pathogenesis, psychosocial factors, and development of novel methods for the study of HIV disease. The Pitt MACS is ideally positioned to address these issues because of long-term standardized follow-up, an extensive repository and an appropriate control group of HIV-uninfected MSM with similar lifestyles, behaviors, and demographics. The Pitt MACS contributes strength and innovation in three areas: (a) studies of viral genomics and host immunopathogenesis including HHV-8/KSHV and HCV coinfections and regulation by host microRNAs, (b) in depth analysis of effects of HIV infection in the brain and lungs including microbiome analysis, and (c) studies of syndemics and resiliencies in aging MSM including effects on depression, substance use and sexual behavior. The Pitt MACS CRS will continue to contribute via the MACS Executive Committee and Working Groups with expertise in all aspects of HIV infection to successfully address our 7 scientific aims that are identical to those in Part A. The Pitt MACS will continue to characterize the long-term, natural and treated history of HIV infection in MSM, provide insight into the clinical epidemiology of HIV, and further our understanding of predictors of disease among HIV positive MSM.